Methods for treating or preventing symptoms of hormonal variations

ABSTRACT

A method for treating or preventing symptoms of hormonal variation includes administering an effective amount of a receptor antagonist to a subject having one or more symptoms of hormonal variations, wherein the receptor antagonist binds to at least one selected from the group consisting of a serotonin type 2A (5-HT 2A ) and a dopamine type 2 (D 2 ) receptors.

This application is a continuation U.S. patent application Ser. No.12/636,552, filed Dec. 11, 2009; which is a continuation U.S. patentapplication Ser. No. 11/638,282, filed Dec. 13, 2006, now U.S. Pat. No.7,645,750. The contents of the above-identified applications areincorporated herein by reference in their entireties.

BACKGROUND OF INVENTION

1. Field of the Invention

The present invention relates generally to treatment or prevention ofsymptoms of hormonal variation, such as hot flashes, night sweats, andinsomnia.

2. Background Art

Hot flashes (also called vasomotor flashes) are the most common symptomsexperienced by women who are perimenopausal or postmenopausal. A hotflash is a sudden sensation of warmth, which is usually accompanied byskin reddening, perspiration, palpitation, anxiety, irritability, andeven panic, and night sweats. A chill may follow a hot flash because ofa subsequent drop in core temperature. Hot flashes vary: they can beseveral times a week or once per hour, they can be characterized by mildwarmth to profuse sweating, and they can last from several seconds to 60minutes. Such symptoms can disrupt sleep and work and interfere withquality of life.

Almost 60-70% of postmenopausal women have hot flashes, andapproximately 10-20% of all postmenopausal women will report intolerablesymptoms, including hot flashes. Some women may suffer from thesesymptoms for up to 15 years (Kronenberg F. “Hot flashes: epidemiologyand physiology,” Ann. N.Y. Acad. Sci., 592:52-86(1990)). Thus, theidentification and proper management of menopausal symptoms are crucialto maintaining a woman's quality of life.

Typical hot flashes occur with sudden onsets of sensation of warmth inthe chest, which then spreads upward to involve the neck and face. Hotflashes can last from a few seconds to several minutes. However, theseverity of the sensations vary greatly both from time to time in thesame woman and from woman to woman. Hot flashes may be accompanied bydizziness, nausea, headaches, palpitations, profuse sweating and nightsweats. How often a woman experiences hot flashes also varies, rangingfrom many times a day to once a week or less. Such symptoms can disruptsleep and work and interfere with quality of life. In some women, hotflashes are provoked by several factors such as hot weather, stress,eating, or drinking alcohol.

Although the pathophysiology of hot flashes is not completelyunderstood, it has been postulated that hot flashes result from atransient lowering of the hypothalamic temperature regulatory set point(Steams et al., “Hot flushes,” Lancet, 360:1851-1861 (2002)). Because ofthe temporal relation between changes in sexual hormone concentrationsand the onset of hot flashes, it is believed that such symptoms resultfrom declining estrogen levels or increased gonadotropin concentrations.Thus, hot flashes occur commonly in menopausal women, but also in womentaking anti-estrogen drugs, such as tamoxifen. Men on androgendeprivation treatment may also experience such symptoms.

Although estrogen replacement therapy can effectively minimize orprevent hot flashes in women, many women are concerned about potentialrisks of hormone replacement therapy. This is especially true for womenwho suffer from breast cancer or have a family history of breast cancer,and/or a history of clotting disorder (Col et al., “Patient-specificdecisions about hormone replacement therapy in postmenopausal women,”JAMA, 277;1140-1147(1997); Gail et al., “The menopause,” Lancet,353:571-580 (1999)).

Various non-hormonal agents have been tested as well, such as clonidine.Clonidine is a centrally-acting α₂ adrenergic receptor agonist. Itselectively stimulates receptors in the brain that monitor catecholaminelevels in the blood. These receptors close a negative feedback loop thatbegins with descending sympathetic nerves from the brain that controlthe production of catecholamines (e.g., epinephrine, also known asadrenaline, and norepinephrine) in the adrenal medulla. By tricking thebrain into believing that catecholamine levels are higher than theyreally are, clonidine causes the brain to reduce its signals to theadrenal medulla, leading to lower catecholamine production. The resultis a lowered heart rate and blood pressure. In randomized clinicaltrials, clonidine was shown to be moderately more efficacious thanplacebo (Goldberg et al., “Transdermal clonidine for amelioratingtamoxifen-induced hot flashes,” J. Clin. Oncol., 12:155-158 (1994);Pandya et al., “Oral clonidine in postmenopausal patients with breastcancer experiencing tamoxifen-induced hot flashes: a University ofRochester Cancer Center Community Clinical Oncology Program study,” AnnIntern Med. 132:788-793 (2000)), but adverse effects are common,including dry mouth, dizziness, and blurred vision.

Recent randomized clinical trials also confirmed that some selectiveserotonin-reuptake inhibitors (SSRI), such as venlafaxine andparoxetine, are more effective than placebo in minimizing the occurrenceand severity of hot flashes (Loprinzi et al., “Venlafaxine in managementof hot flashes in survivors of breast cancer: a randomized controlledtrial,” Lancet 356:2059-2063 (2000); Stearns et al., “Paroxetinecontrolled release in the treatment of menopausal hot flashes: Arandomized controlled trial,” JAMA 289:2827-2834 (2003)). However,adverse effects with SSRIs are moderate, including headache, agitation,tremor, sedation, and sexual dysfunction.

Given the risks of estrogen replacement therapy and marginal benefits ofcurrent non-hormonal treatments, there is a continued need foralternative methods or drugs for treating or preventing symptomsassociated with menopause, including hot flashes.

SUMMARY OF INVENTION

In one aspect, embodiments of the invention relate to methods fortreating or preventing symptoms of hormonal variation. A method inaccordance with one embodiment of the invention includes administeringan effective amount of a receptor antagonist to a subject having one ormore symptoms of hormonal variations, wherein the receptor antagonistbinds to at least one selected from the group consisting of a serotonintype 2A (5-HT_(2A)) receptor and a dopamine type 2 (D₂) receptor. Thereceptor antagonist is one selected from risperidone, quetiapine,clozapine, olanzapine, aripiprazole, ziprasidone, zotepine, and9-hydroxyrisperidone.

Other aspects and advantages of the invention will become apparent fromthe following description and attached claims.

DETAILED DESCRIPTION

Embodiments of the invention relate to methods for treating orpreventing symptoms associated with hormonal variations, particularlythose associated with hormonal changes accompanying menopause. In thefollowing description, numerous details are set forth to provide anunderstanding of the present invention. However, it would be understoodby those skilled in the art that the present invention may be practicedwithout these details and that numerous variations or modifications fromthe described embodiments are possible without departing from the scopeof the invention. The methods of the invention may involve administeringan effective amount of a therapeutic agents by oral administration,injection, inhalation, transdermal patch, or any other routes commonlyused in the art.

Furthermore, the following describes several examples to illustrateembodiments of the invention. These examples are for illustrativepurpose only. One of ordinary skill in the art would appreciate thatthese examples are not exhaustive and they are not intended to limit thescope of the invention. In addition, it should be understood thatthroughout this specification, when a concentration or amount range isdescribed as being useful, or suitable, or the like, it is intended thatany and every concentration or amount within the range, including theend points, is to be considered as having been stated. Furthermore, eachnumerical value should be read once as modified by the term “about”(unless already expressly so modified) and then read again as not to beso modified unless otherwise stated in context. For example, “a range offrom 1 to 10” is to be read as indicating each and every possible numberalong the continuum between about 1 and about 10. In other words, when acertain range is expressed, even if only a few specific data points areexplicitly identified or referred to within the range, or even when nodata points are referred to within the range, it is to be understoodthat the inventors appreciate and understand that any and all datapoints within the range are to be considered to have been specified, andthat the inventor have possession of the entire range and all pointswithin the range.

Although menopause is a natural process that occurs in women's lives aspart of normal aging. Some women go through these courses with fewsymptoms, while others have significant or even disabling symptoms suchas hot flashes. Hot flashes are generally systemic and likely resultfrom an alteration in the thermoregulatory set-point centre, which islocated in the pre-optic anterior hypothalamus, with involvement ofdopamine, serotonin, nor-epinephrine, and alpha-adrenergic receptors.(Steams et al., “Hot flushes,” Lancet 360:1851-1861 (2002)).

Among various receptors, inventor of the present invention had foundthat specific subtypes of dopamine, serotonin, and a adrenergicreceptors are effective targets for the treatment of hot flashes andother symptoms associated with hormonal variations. Specifically,5-HT_(2A) antagonist and/or D₂ dopamine antagonist are found to beeffective in reducing or eliminating symptoms associated with hormonalvariations.

Thus, in accordance with some embodiments of the invention, a method fortreating or preventing symptoms of hormonal variations may comprise theuse of an effective amount of an antagonist of 5-HT_(2A) serotoninreceptor and/or D₂ dopamine receptor. An effective amount of anantagonist that binds 5-HT_(2A) and/or D₂ receptors will depend on themode of administration, frequency of administration, and the type ofpharmaceutical composition used to deliver the compound into a patient,as well as weight, gender, age, and physical conditions of the patient.Generally, effective amounts of such compounds will be about 0.002 mg toabout 0.5 mg/kg body weight per day, preferably about 0.005 mg to 0.1mg/kg body weight per day, and more preferably about 0.005 to about0.034 mg/kg body weight per day. For example, daily doses may range fromabout 0.1 to about 25 mg per day for an adult patient weighing about 50Kg (110 lb), or from about 0.2 to about 50 mg per day for an adultpatient weighing about 100 Kg (220 lb). While individual needs vary,determination of optimal range of effective amounts of each compound iswithin the skills of one skilled in the art. By treating the symptoms ofhormonal variations, including hot flashes, embodiments of the inventioneither reduce the number (occurrence or frequency), duration, and/orseverity of symptomatic events. Administering a compound of theinvention to a patient may be via any suitable route used foradministering similar pharmaceuticals to a patient, including oraladministration, injection, and transdermal patch, to name a few. Thecompound may be administered with any pharmaceutically acceptablecarrier or excipient.

Serotonin (5-HT) receptors comprise about 15 different receptors. Type 2(5-HT₂) serotonin receptors are G_(q)/G₁₁ coupled receptors that mediatecellular effects by increasing cellular levels of inositol triphosphate(IP₃) and diacylglycerol (DAG). In accordance with some embodiments ofthe invention, serotonin type 2A receptor is the target for treating orpreventing symptoms associated with hormonal variation. Rreduction in5-HT levels increases the sensitivity of 5-HT_(2A) receptor in thehypothalamus, which is involved in thermoregulation. Therefore,modulators of 5-HT_(2A) receptors may be useful in the management ofsymptoms associated with hormone variations.

In accordance with one embodiment of the invention, risperidone may beused to treat symptoms of hormonal variations. Risperidone (Belivon®,Rispen®, Risperdal® in the United States) is an antipsychotic medicationthat functions by interfering with the communication among nerves in thebrain. Risperidone acts as a 5-HT_(2A) antagonist and can be used toquickly and effectively block the effects of 5-HT_(2A) agonists at a lowdose. Risperidone is also a potent dopamine type 2 (D₂), and α₂adrenergic receptor antagonist. Thus, risperidone has been used in thetreatment of psychotic disorders, for example, schizophrenia. However,as described in the following sections, risperidone has beenunexpectedly found to be effective in reducing or eliminating symptomsassociated with hormonal variations.

In accordance with another embodiment of the invention,9-hydroxyrisperidone may be used as a treatment for the symptoms ofhormonal variations. 9-Hydroxyrisperidone is the principal activemetabolite of risperidone, and they had similar binding profiles andaffinity for 5-HT_(2A) receptors and D₂ receptors.(Leysen et al.,“Risperidone: a novel antipsychotic with balanced serotonin-dopamineantagonism, receptor occupancy profile, and pharmacologic activity,” JClin Psychiatry: 55 Suppl: 5-12 (1994)). Like risperidone,9-hydroxyrisperidone can effectively treat or prevent the symptomsassociated with hormonal variations its antagonist activity for5-HT_(2A) and/or dopamine receptors.

In addition to risperidone and 9-hydroxyrisperidone, other receptorantagonists that can bind to 5-HT_(2A) and/or D₂ dopamine receptors mayalso be used to control symptoms associated with hormonal variations.These other antagonists, for example, may include quetiapine, clozapine,olanzapine, aripiprazole, ziprasidone, and zotepine.

In accordance with another embodiment of the invention, quetiapine maybe used as a treatment for the symptoms of hormonal variations. Theantipsychotic effect of quetiapine is thought to be mediated by itsantagonist activity against dopamine and 5-HT receptors. Specifically,dopamine receptors D₁, D₂, and 5-HT receptors, 5-HT_(1A) and 5-HT₂subtypes, are antagonized.

Serial PET scans evaluating the D₂ dopamine receptor occupancy ofquetiapine have revealed that quetiapine rapidly disassociates from theD₂ receptor. Theoretically, this allows for normal physiological surgesof dopamine to elicit their normal effects in areas such as thenigrostriatal and tuberoinfundibular pathways, thus minimizing the riskof side effects such as pseudo-Parkinsonism and elevations in prolactin.Quetiapine also has an antagonistic effect on the H₁ histamine receptor.This may be responsible for the sedative effect of the drug.

In accordance with some embodiments of the invention, clozapine may beused as a treatment for the symptoms of hormonal variations. Clozapineis classified as an ‘atypical’ antipsychotic drug because its profile ofbinding to dopamine receptors and its effects on variousdopamine-mediated behaviors differ from those exhibited by more typicalanti-psychotics. In particular, clozapine has a high affinity for the D4receptor and it also interferes to a lower extent with the binding ofdopamine with D₁, D₂, D₃ and D₅ dopamine receptors. However, clozapinedoes not induce catalepsy, nor does it inhibit apomorphine-inducedphenotype in animal models seen with ‘conventional’ neuroleptics. Thisevidence suggests that clozapine is preferentially more active at limbicthan at striatal dopamine receptors and may explain its relatively mildextra-pyramidal side effects and its strong anti-cholinergic activity.Clozapine is also a strong antagonist of different subtypes ofadrenergic, cholinergic, histaminergic and serotonergic receptors.

In accordance with some embodiments of the invention, olanzapine may beused as a treatment for symptoms of hormonal variations. Olanzapine isstructurally similar to clozapine, and has a high affinity for dopamineand serotonin receptors. Olanzapine has a low affinity for histamine,cholinergic muscarinic and α-adrenergic receptors. The mechanism ofaction of olanzapine is unknown. However, it is thought thatolanzapine's antipsychotic activity is mediated primarily by antagonismof dopamine receptors, specifically D₂ dopamine receptor. 5-HTantagonism may also play a role in the effectiveness of olanzapine.However, the significance of 5-HT_(2A) antagonism is debated amongresearchers. In accordance with some embodiments of the invention,aripiprazole may be used as a treatment of symptoms of hormonalvariations. Aripiprazole (Abilify® from Bristol-Myers Squibb) is a newatypical antipsychotic medication awaiting approval by the FDA for thetreatment of schizophrenia. Aripiprazole has been approved by the FDAfor the treatment of acute manic and mixed episodes associated withbipolar disorder. Aripiprazole appears to mediate its antipsychoticeffects primarily by acting as a partial agonist of the D₂ receptor.Partial agonism at D₂ receptors has been shown to modulate dopaminergicactivity in areas where dopamine activity may be high or low, such asthe mesolimbic and mesocortical areas of the schizophrenic brain,respectively. In addition to partial agonist activity of the D₂receptor, aripiprazole is also a partial agonist of the 5-HT_(1A)receptor Like other atypical anti-psychotics, aripiprazole exhibitsantagonist activities against the 5-HT_(2A) receptor. Aripiprazole hasmoderate affinities for histamine and .alpha.-adrenergic receptors, butno appreciable affinity for cholinergic muscarinic receptors.

In accordance with some embodiments of the invention, ziprasidone may beused as a treatment of symptoms of hormonal variations. Ziprasidone hasa high affinity for dopamine, serotonin, and alpha-adrenergic receptorsand a moderate affinity for histaminic receptors. Ziprasidone issomewhat unique among the “atypicals” in that it can also inhibitsynaptic reuptake of serotonin and norepinephrine, although the clinicalsignificance of this is unknown. The mechanism of action of ziprasidoneis unknown. However, it is thought that its antipsychotic activity ismediated primarily by its antagonism against dopamine receptors,specifically D₂ dopamine receptor. Serotonin antagonism may also play arole in the effectiveness of ziprasidone, but the significance of5-HT_(2A) antagonism of ziprasidone is debated among researchers.Antagonism at histaminic and alpha adrenergic receptors likely explainssome of the side effects of ziprasidone, such as sedation andorthostasis.

In accordance with some embodiments of the invention, zotepine may beused as a treatment of symptoms of hormonal variations. Zotepine has ahigh affinity for the D₁ and D₂ dopamine receptors. It also affects the5HT2_(A), 5HT2_(C), 5HT₆, and 5HT₇ receptors. In addition, it can alsoinhibit the reuptake of noradrenaline.

Clinical Examples

The following examples are provided to illustrate that embodiments ofthe present invention can reduce the symptoms of hormone variations,including hot flashes, night sweats, and blood pressure fluctuations.Embodiments of the invention are effective for patients under variousconditions. However, one of ordinary skill in the art would appreciatethat these examples are for illustration only and by no means areintended to limit the scope of the invention.

Embodiments of the invention involve administering a therapeuticallyeffective amount of an antagonist (such as risperidone or9-hydroxyrisperidone) of 5-HT_(2A) and/or D₂ dopamine receptor toalleviate symptoms associated with hormone variations. For example,risperidone has been used on several patients to successfully alleviatethe occurrence of hot flashes or other symptoms of hormonal variations.The following describe four specific examples from four differentpatients to illustrate the effectiveness of risperidone in alleviatingsymptoms associated with hormone variations. One of ordinary skill inthe art would appreciate that these specific examples are not intendedto limited the scope of the invention. For example, embodiments of theinvention may use other regimens, including other antagonists of5-HT_(2A) and/or D₂ dopamine receptors.

Patient 1: Risperidone Resolved Hot Flashes in a Case with Hysterectomy

A 68-year-old woman was admitted to the hospital in December of 2004 dueto hot flashes, hypertension, and restlessness. She had been told thatshe was suffering from essential hypertension for 16 years and had takenanti-hypertension medications for several years. However, her bloodpressure still fluctuated and frequently dropped below critical levelafter taking sublingual adalate (10 mg) for sudden onsets of high bloodpressure. She had no history of psychiatric or systemic diseases, exceptfor a total abdominal hysterectomy at age 45. On admission, it wasobserved that her hot flash attacks occurred many times a day, lasting afew minutes and was usually followed by high blood pressure up to180-200/84-96 mmHg, general shivers, and anxiety for 20-60 minutes. Suchclinical symptoms started around age 50 and grew progressively worse.

Her biochemical and hematological results, such as sodium and potassiumlevels, 140 mmol/L and 4.0 mmol/L, respectively, were all within normalranges. Plasma cortisol levels were within the normal range and showeddiurnal rhythm. The plasma adrenaline, nor-adrenaline, VMA, epinephrine,and dopamine levels as well as thyroid hormones, including T3, T4, andTSH, were also normal. SSR and RRIV tests to assess sympathetic andparasympathetic functions, respectively, demonstrated her autonomicnervous system was normal. EEG showed no focal epileptiform dischargesnor abnormal background activities. Brain MRI showed aging brainchanges, but no lesion in hypothalamus or brain stem. 24-hour Holter'sscan showed normal sinus rhythm. Echocardiography demonstrated normalcardiac chamber size, normal LV systolic performance, and wall motion.

After one month of observation, the patient received treatments ofPremarin® 0.625 mg/day, Prozac® 20 mg/day and Tofranil® 20 mg/day, eachfor 1-2 months with limited success. Because estrogen withdrawal mayalter the thermoregulatory set-point located in the hypothalamus, byincreasing the sensitivity of hypothalamic 5-HT2A receptor, a regimen ofa 5-HT_(2A) antagonist may provide an effective therapy for symptoms ofhormonal variations, such as hot flashes. Thus, the patient was treatedwith risperidone (2 mg/day). After three days of treatment, her hotflashes reduced markedly to a frequency of once per 1-2 weeks.Associated symptoms, such as palpitation and anxiety, also improvedsignificantly. Thereafter, the dosage of anti-hypertension drugs wasreduced. With the patient's permission, risperidone therapy wasdiscontinued and hot flashes reoccurred within 2-3 days afterdiscontinuing the treatment. The symptoms were again alleviated 3-4 daysafter resuming risperidone treatment.

Patient 2: Risperidone Resolved Hot Flashes of Natural Menopause

Patient 2 was a 57-year-old woman who began developing intolerable hotflashes and night sweats after natural menopause that occurred sevenyears ago. Although she responded well to hormone replacement therapy(Premarin® 0.625 mg per day), she discontinued the therapy one yearprior to this study because she was concerned about the potential riskof breast cancer. One month after discontinuing hormone replacementtherapy, she developed hot flashes up to ten times per day, night sweatsup to three times per night that disrupted her sleep, and headaches. Thepatient then sought neurological consultation. The patient also sufferedfrom headaches twice per day and fluctuating blood pressure. Risperidonewas started at a dose of 2 mg per day and the patient reported that theoccurrence of hot flashes reduced markedly two days after startingrisperidone treatment and was completely eliminated by day 7. Inaddition, she slept well and her blood pressure stabilized. To assessthe relationship between risperidone therapy and the resolution of hotflashes, risperidone was tapered off over 2 days. The patientexperienced hot flashes and night sweats again two days afterrisperidone treatment was completely discontinued. Risperidone 2 mgdaily was resumed and the patient has not suffered another hot flashsince.

Patient 3: Risperidone Resolved Hot Flashes in a Perimenopausal Case

Patient 3 was a 46-year-old woman who was diagnosed with perimenopause,based on increased levels of follicle-stimulating hormone, increasedvariability in menstrual cycle length, development of hot flashes, andinsomnia. The patient had had these symptoms for two years. Sheresponded well to estrogen therapy. Because of health risks, the patientdiscontinued estrogen treatment and sought supplementary therapy, suchas soy isoflavones, but without success. Risperidone treatment (1 mg pernight) was started. At that time, the patient was experiencing seven hotflashes per day. The patient reported that the frequency and intensityof her hot flashes were markedly reduced three days after startingrisperidone therapy. With her permission, risperidone was tapered offover two days, and the hot flashes developed again three days later.After risperidone treatment (1 mg daily) was resumed, the patient nolonger experienced hot flashes, and the quality of her sleep and herlife improved. Three months later, the dosage of risperidone wasdecreased to 0.25 mg or less per day, and the patient's hot flashes werestill markedly eliminated

Patient 4: Risperidone Resolved Residual Hot Flashes in a Case withHormone Replacement Therapy

Patient 4 was a 56-year-old woman who had developed hot flashes, with afrequency of once per hour, palpitation, insomnia, headache,restlessness, and unstable blood pressure for over seven years.Initially, the patient visited a psychiatrist for her sleep disorder anda cardiovascular specialist for her high blood pressure. A year later,because of intolerable hot flashes and other menopausal symptoms, shereceived hormone replacement therapy (Divina®)). Although her hotflashes were reduced to twice per day, headaches persisted and her bloodpressure fluctuated from 180 to 210/110 to 90 mm Hg despite treatmentwith anti-hypertension drugs. The patient was started on risperidonetreatment, 1 mg at bedtime for the first two days, followed by 2 mg pernight, for residual hot flashes. The patient's hot flashes werecompletely eliminated three days after starting the risperidone therapy.Additionally, the patient was able to take hormone four times a day anddiscontinue the use of all anti-hypertension drugs because her bloodpressure stabilized within the normal range.

The above data clearly show that risperidone or similar receptorantagonists are effective in alleviating the symptoms associated withhormonal variations, such as hot flashes and blood pressurefluctuations. It is also contemplated that administration of a compoundof the invention for alleviating symptoms associated with hormonalvariations may be carried out in combination with other suitabletherapeutic treatments which are useful for treating symptoms ofhormonal variations, including hot flashes.

While not intended to be bound by the mechanisms of how these receptorantagonists function to alleviate symptoms associated with hormonalvariations, the inventor believes these drugs probably function byinhibiting 5-HT_(2A) serotonin receptor, D₂ dopamine receptor, and/orα₁-adrenergic receptor.

Menopause is a natural process that occurs in women's lives as part ofnormal aging. Approximately one-third of women experience few or nosymptoms, while the remaining may have significant or even disablingsymptoms such as severe hot flashes. Hot flashes are generally systemicand likely result from an alteration in the thermoregulatory set-pointcentre, which is located in the pre-optic anterior hypothalamus, withinvolvement of dopamine, serotonin, nor-epinephrine, andalpha-adrenergic receptors (Steams et al., “Hot flashes,” Lancet360;1851-1861 (2002)).

Risperidone, a benzisoxazole derivative, is an atypical antipsychoticdrug, which binds with high affinity to the serotonin type 2A 5-HT_(2A),dopamine type 2 (D₂), and α₁-adrenergic receptors. Risperidone bindswith lower affinities to the α₂-adrenergic and H₁ histamine receptors.Risperidone does not bind to D₁ dopamine receptors and has no affinity(when tested at concentrations >10⁻⁵ M) for muscarinic cholinergicreceptors. (Grant and Fitton, “Risperidone. A review of its pharmacologyand therapeutic potential in the treatment of schizophrenia,” Drug,48:253-273 (1994); Ota et al., “Peripheral injection of risperidone, anatypical antipsychotic, alters the body weight gain of rats,” Clin Exppharmacol. physiol., 29:980-989 (2002)).

Experimental data suggest that stimulation of 5-HT2 and dopaminereceptors can increase body temperatures. For example, directstimulation of 5-HT_(2A) receptors can also induce hyperthermia inanimal models, while administration of 5-HT_(2A) antagonists can preventhyperthermia in the animal model for serotonin syndrome. However,administration of 5-HT_(1A) agonists to rodent or human leads to areduction in core body temperature. These results suggest that the two5-HT receptor subtypes, 5-HT_(1A) and 5-HT_(2A), are closely associatedwith body temperature control (Oether et al., “Involvement of 5-HT_(1A)and 5-HT_(1B) receptors for citalopram-induced hypothermia in the rat,”Psychopharmacology, 154:429-434 (2001); Salmi and Ahlenius, “Evidencefor functional interactions between 5-HT_(1A) and 5-HT_(2A) receptors inrat thermoregulatory mechanisms,” Pharmacol. Toxicol., 82:122-127(1998)).

During menopause, a marked decline in sexual hormones, especiallyestrogen levels, may lead to a significant reduction in blood serotonin(5-HT) levels. The reduction in serotonin levels increases thesensitivity of the 5-HT_(2A) receptors in the hypothalamus (Berendsen HH, “The role of serotonin in hot flashes,” Maturiatas, 36:155-164(2000)). Thus, when an internal and an external stimulus, such asanxiety, induces the release of serotonin to stimulate the enhancedsensitivity 5-HT_(2A) receptors, the set-point for body temperature ischanged and hot flashes occur.

Pulsatile luteinizing hormone (LH) secretion theory is another commonexplanation for the development of hot flashes because administration ofLH-RH agonist can result in hot flashes. The dopaminergic system seemsto be involved in both pulsatile LH secretion and hot flashes inpost-menopausal women. Anti-dopaminergic drugs could act on thethermoregulatory nucleus to reduce hot flashes by directly decreasingadrenergic effects on the thermoregulatory nucleus, or indirectlythrough mechanisms such as the short-loop feedback exerted byhyperprolactinaemia on the tuberoinfundibular dopamine neurons with asecondary dopamine-like activity, or by stimulating the opioid system(Melis G B et al., “Effects of the dopamine antagonist veralipride onhot flashes and luteinizing hormone secretion in postmenopausal somen,”Obstet. Gynecol. 72:688-692 (1988); Wesel et al., Veralipride versusconjugated oestrogens: a double-blind study in the management ofmenopausal hot flashes,” Curr. Med. Res. Opin., 8:696-700 (1984)).

Risperidone has high affinities for 5-HT_(2A) and D₂ receptors.Risperidone can counteract enhancement of 5-HT activity as well asdecrease nor-epinephrine activity in the anterior hypothalamus in theserotonin syndrome (Nisijima et al., “Risperidone counteracts lethalityin an animal model of the serotonin syndrome,” Psychopharmacology150:9-14 (2000)). In addition, risperidone may elevate circulatingprolactin levels in healthy subjects and schizophrenic patients(Markianos et al., “Neuroendocrine serotonergic and dopaminergicresponsivity in male schizophrenic patients during treatment withneuroleptics and after switch to risperidone,” Psychopharmacology,157:55-59 (2001)). Risperidone can also reduce or prevent hot flashesthrough anti-dopaminergic effects on the loop of tuberoinfundibulardopamine neurons and on nor-epinephrine activity in the anteriorhypothalamus.

Advantages of embodiments of the invention may include one or more ofthe following. Embodiments of the invention can provide compositions andmethods for the treatment of the symptoms of hormonal variationsincluding hot flashes and night sweats. Additionally, these methods andcompositions can also achieve normalization of blood pressure andelimination/reduction of palpitations. Compositions of the invention maycomprise a serotonin type 2A (5-HT_(2A)) receptor, dopamine type 2 (D₂)receptor, and/or α₁-adrenergic receptor antagonist and can provide aplethora of treatment options for improving the quality of life of womenexperiencing the symptoms of hormonal variations.

While the invention has been described with respect to a limited numberof embodiments, those skilled in the art will appreciate that otherembodiments can be devised which do not depart from the scope of theinvention as disclosed herein. Accordingly, the scope of the inventionshould be limited only by the attached claims.

What is claimed is:
 1. A method for treating or preventing symptoms ofhormonal variation, comprising: administering an effective amount of areceptor antagonist to a subject having one or more symptoms of hormonalvariations, wherein the receptor antagonist binds to at least oneselected from the group consisting of a serotonin type 2A (5-HT_(2A))receptor and a dopamine type 2 (D₂) receptor, and wherein the symotomsof hormonal variation are associated with perimenonause orpostmenopause.
 2. The method of claim 1, wherein the symptoms ofhormonal variation comprises at least one selected from hot flashes,dizziness, nausea, headaches, palpitations, profuse sweating, and nightsweats.
 3. The method of claim 1, wherein the receptor antagonist is atleast one selected from risperidone, 9-hydroxyrisperidone, quetiapine,clozapine, olanzapine, aripiprazole, ziprasidone, and zotepine.
 4. Themethod of claim 3, wherein the effective amount of the receptorantagonist is from 0.1 to 50 mg per day for an adult patient.
 5. Themethod of claim 3, wherein the effective amount of the receptorantagonist is from 0.1 to 20 mg per day for an adult patient.
 7. Themethod of claim 3, wherein the effective amount of the receptorantagonist is from 0.1 to 6 mg per day for an adult patient.
 8. Themethod of claim 3, wherein the effective amount of the receptorantagonist is from 0.1 to 2 mg per day for an adult patient.
 9. Themethod of claim 1, wherein the effective amount of the receptorantagonist is administered by using a pharmaceutically acceptableformulation.
 10. The method of claim 9, wherein the pharmaceuticallyacceptable formulation is an oral formulation, injection, inhalation, ortransdermal patch.